The androgen receptor (AR) is member of the steroid hormone receptor superfamily. Upon binding to its ligand androgen, AR functions as a transcription factor to induce expression of numerous genes, thereby regulating many physiological or pathological activities, from cell proliferation, tumorigenesis, to neurodegenerative disorders. However, the ligand-independent function of AR was unknown and the role of AR in programmed cell death is also incompletely understood. Recently, we uncovered that AR can promote UV-induced pro-death activity of the Bcl-2 family protein Bax through its non-transcription activity, but inhibits tumor necrosis factor (TNF1)-induced pro-death activity of the MAP kinase JNK through its transcription activity. We hypothesize that AR has dual regulatory role in programmed cell death: promoting or inhibiting apoptosis in a death stimulus-dependent manner. In this proposal, we will first determine the mechanism by which AR promotes Bax-dependent cell death through its non-transcription activity. To this end, we will define the AR pro-death domain(s) that is sufficient to promote Bax pro-death activity and determine whether AR regulates the interaction between Bax and other Bcl-2 family members, thereby promoting Bax activation. Finally, we will study whether specific AR-dependent Bax-associated proteins are involved in AR-mediated cell death, and determine whether the promotion of Bax activity by AR sensitizes cell death in animal model. Next, we will determine the mechanism by which AR inhibits TNF1-induced, JNK-dependent cell death through its transcription activity. To this end, we will determine how androgen/AR via induction of p21 inhibits TNF1-induced JNK activation and whether inhibition of JNK activity by androgen/AR occurs in animal model. We will determine whether in addition to inhibition of JNK, androgen/AR suppresses TNF1-induced cell death through inhibition of other component(s) in the death machinery. Finally, we will determine how differential regulation of JNK and Bax by AR is integrated for suppressing TNF1- induced cell death. Our long-term goal is to uncover the molecular mechanism underlying the ligand-independent function of AR and its differential regulation of programmed cell death, thereby providing molecular basis for developing novel strategies to treat human diseases related to dysregulation of AR function. PROJECT NARRATIVE: The androgen receptor involves many physiological or pathological activities, from cell proliferation, tumorigenesis, to neurodegenerative diseases. In this proposal, we will study molecular mechanisms underlying the non-transcription function of AR and its dual regulatory roles in cell death in response to different death stimuli. This study should provide invaluable information for developing novel strategies for prevention and treatment of human diseases, such as prostate cancer and spinal and bulbar muscular atrophy.